I. Drug Name

Generic Name: Crizotinib Capsules

English Name: Crizotinib

Brand Names: Xalkori, Saikerui, Kesodx

Dosage Form: Oral Capsules

Specification: 250 mg per capsule; 60 capsules per box

Manufacturer: Laos Big Bear Pharmaceutical Co., Ltd.

Regulatory Approval No.: 08 L1071/24

II. Pharmacological Actions

Pharmacological Classification: Receptor Tyrosine Kinase Inhibitor

Mechanism of Action: Crizotinib is a selective, orally bioavailable small-molecule inhibitor that primarily targets:

Anaplastic Lymphoma Kinase (ALK)

ROS1 (c-ros oncogene 1)

In ALK-positive or ROS1-positive tumors, the corresponding genes undergo rearrangement, producing abnormal fusion proteins that constitutively activate signaling pathways driving tumor cell growth, proliferation, and survival.

By inhibiting the activity of ALK and ROS1 kinases, Crizotinib blocks these abnormal signals, thereby inducing tumor cell apoptosis and inhibiting tumor growth.

III. Indications

Crizotinib is indicated for the treatment of the following patients:

1. ALK-positive Non-Small Cell Lung Cancer (NSCLC):

For the treatment of adult and pediatric patients with ALK-positive, locally advanced or metastatic non-small cell lung cancer.

2. ROS1-positive Non-Small Cell Lung Cancer (NSCLC):

For the treatment of adult patients with ROS1-positive, metastatic non-small cell lung cancer.

IV. Dosage and Administration

Recommended Dosage: 250 mg, twice daily (approximately every 12 hours), taken orally.

May be taken with or without food.

Method of Administration: Swallow the capsules whole.

If a dose is missed, it should be taken immediately unless less than 6 hours remain before the next scheduled dose. Do not take a double dose to make up for a missed dose.

If vomiting occurs after taking a dose, do not take a replacement dose; wait until the next scheduled time to take the regular dose.

V. Contraindications

Patients with a history of severe hypersensitivity to Crizotinib or to any of the excipients. VI. Warnings and Precautions

1. **Hepatotoxicity:**

May cause fatal hepatotoxicity.

ALT (alanine aminotransferase), AST (aspartate aminotransferase), and total bilirubin levels must be monitored prior to initiating treatment, at least once monthly during the first two months of treatment, and periodically thereafter as clinically indicated.

Depending on the severity of the hepatotoxicity, treatment may require interruption, dose reduction, or permanent discontinuation.

2. **Interstitial Lung Disease (ILD)/Pneumonitis:**

Severe, and potentially fatal, ILD/pneumonitis may occur.

Patients presenting with treatment-related pulmonary symptoms should immediately interrupt treatment and undergo an evaluation for ILD/pneumonitis. If diagnosed, crizotinib must be permanently discontinued.

3. **QT Interval Prolongation:**

May cause concentration-dependent prolongation of the QTc interval, increasing the risk of *Torsades de Pointes*.

Monitor ECGs and electrolytes (e.g., potassium, magnesium, calcium) prior to initiating treatment and periodically during treatment.

More frequent monitoring is required for patients at risk of QTc interval prolongation. Depending on the severity of the QTc interval prolongation, treatment may require interruption, dose reduction, or permanent discontinuation.

4. **Bradycardia:**

May cause symptomatic bradycardia (slow heart rate).

Monitor heart rate and blood pressure periodically during treatment. Depending on the severity, treatment may require interruption, dose reduction, or permanent discontinuation.

5. **Severe Visual Impairment:**

Visual disorders—such as blurred vision, diplopia (double vision), photopsia (flashing lights), decreased visual acuity, or visual field defects—may occur.

Patients should be advised to report any changes in vision. If severe visual impairment occurs, treatment should be interrupted and an ophthalmologic evaluation performed.

6. **Embryo-Fetal Toxicity:**

Based on its mechanism of action, this drug may cause fetal harm when administered to pregnant women.

Females of reproductive potential should use effective contraception during treatment and for at least 45 days following the last dose.

Male patients with female partners who are pregnant or of reproductive potential should use effective condoms during treatment and for at least 90 days following the last dose. VII. Adverse Reactions

Very Common (>10%) Serious and/or Major Adverse Reactions:

Visual Disorders: Blurred vision, diplopia, visual flashes (typically Grade 1–4).

Gastrointestinal: Nausea, diarrhea, vomiting, constipation, esophageal disorders (dysphagia/pain).

Hepatobiliary System: Elevated ALT/AST.

Nervous System: Peripheral neuropathy, dizziness, dysgeusia.

Respiratory System: Upper respiratory tract infection.

Systemic: Edema (peripheral edema, facial edema), fatigue.

Laboratory Abnormalities: Lymphopenia, neutropenia, hypophosphatemia.

Common but Serious Adverse Reactions:

Hepatic injury, ILD/pneumonitis, QT interval prolongation, bradycardia, heart failure.

VIII. Drug Interactions

Strong CYP3A Inhibitors (e.g., clarithromycin, itraconazole, ritonavir):

Co-administration significantly increases crizotinib plasma concentrations, thereby increasing the risk of adverse reactions.

Avoid co-administration. If co-administration is unavoidable, consider reducing the crizotinib dosage to 200 mg once daily.

Strong CYP3A Inducers (e.g., rifampin, phenytoin, carbamazepine, St. John's wort):

Co-administration significantly decreases crizotinib plasma concentrations, potentially leading to a loss of efficacy.

Avoid co-administration.

CYP3A Substrates:

Crizotinib is a moderate inhibitor of CYP3A; it may increase the plasma concentrations of drugs metabolized via CYP3A (e.g., midazolam, alfentanil, certain statins).

Monitor closely for adverse reactions associated with these substrate drugs during co-administration.

IX. Use in Specific Populations

Pregnant Women: May cause fetal harm. Advise pregnant women of the potential risk to the fetus.

Lactating Women: Advise women to discontinue breastfeeding during treatment and for 45 days following the last dose.

Pediatric Patients: Approved for use in pediatric patients with ALK-positive NSCLC. Geriatric Patients: In patients aged 65 years and older, no significant differences in overall safety were observed compared to younger patients.

Patients with Hepatic/Renal Impairment:

Hepatic Impairment: No dose adjustment is required for patients with mild (Child-Pugh A) or moderate (Child-Pugh B) hepatic impairment. For patients with severe (Child-Pugh C) hepatic impairment, the recommended dose is 250 mg once daily.

Renal Impairment: No dose adjustment is required for patients with mild to moderate renal impairment (creatinine clearance 30–89 mL/min). For patients with severe renal impairment (creatinine clearance <30 mL/min) or those requiring dialysis, data on drug use are limited; therefore, caution is advised, and the recommended dose is 250 mg once daily.

X. Overdosage

Symptoms: Overdosage is expected to result in an exacerbation of adverse reactions, such as severe nausea, vomiting, diarrhea, visual disturbances, QT interval prolongation, etc.

Management: The drug should be discontinued immediately. Supportive care and symptomatic treatment should be initiated, and the patient's ECG and vital signs should be closely monitored.

XI. Clinical Pharmacology

Pharmacokinetics: Crizotinib is well absorbed following oral administration, reaching peak plasma concentrations approximately 4–6 hours after dosing. Administration with food may increase its absorption. In vivo, the drug is primarily metabolized via CYP3A4/5. Fecal excretion is the primary route of elimination.

XII. Patient Counseling Information

1. Genetic Testing: Patients must understand that ALK or ROS1 gene testing is mandatory prior to initiating treatment.

2. Adherence to Prescribing Instructions: Take the medication strictly according to the dosage and schedule prescribed by your physician.

3. Visual Changes: Be aware that visual disturbances may occur; exercise caution when driving or operating machinery. Report any severe changes in vision to your physician immediately.

4. Regular Monitoring: Understand the importance of regular monitoring of liver function, ECG, heart rate, and electrolytes.

5. Pulmonary Symptoms: Immediately report any new or worsening pulmonary symptoms, such as difficulty breathing, coughing, or fever.

6. Contraception Requirements: Patients of reproductive potential must understand and strictly adhere to the prescribed contraception requirements.

Final Reminder: Please be sure to follow the specific instructions provided by your treating physician and pharmacist. If you have any questions or experience any discomfort during treatment, please communicate immediately with your medical team.

**Product Specifications**

**Product Name:** Crizotinib Capsules 250mg * 60 Capsules/Box (Kesodx Crizotinib)

**Common Name:** Crizotinib Capsules

**Composition:** Crizotinib

**Dosage Form:** Capsules

**Specification:** 250mg per capsule; 60 capsules per box

**Manufacturer:** Lao Da Xiong Pharmaceutical Co., Ltd.

**Indications:** 1. ALK-positive Non-Small Cell Lung Cancer (NSCLC):

Used for the treatment of adult and pediatric patients with ALK-positive, locally advanced or metastatic non-small cell lung cancer.

2. ROS1-positive Non-Small Cell Lung Cancer (NSCLC):

Used for the treatment of adult patients with ROS1-positive, metastatic non-small cell lung cancer.

**Dosage and Administration:** Recommended dosage: 250mg, twice daily (approximately every 12 hours), taken orally.

May be taken with or without food.

**Administration Method:**

Swallow the capsules whole.

If a dose is missed, take the missed dose immediately unless fewer than 6 hours remain before the next scheduled dose. Do not take a double dose to make up for a missed dose.

If vomiting occurs after taking the medication, do not take an additional dose; wait until the next scheduled time to take the regular dose.